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Relation of serotonin transporter genetic variation to efficacy of escitalopram for generalized anxiety disorder in older adults.

ABSTRACT: OBJECTIVE:Generalized anxiety disorder (GAD) is common in older adults and can be treated with selective serotonin reuptake inhibitors (SSRIs). Genetic variation in the serotonin transporter gene promoter region is posited to be associated with SSRI efficacy: 2 polymorphisms (5-HTTLPR S/L and rs25531 g/a) form a haplotype with the La combination having higher transcription activity than other haplotypes. We hypothesized that GAD patients with no La haplotypes (La?) have lower SSRI treatment efficacy than those with 1 to 2 La haplotypes (La+). METHOD:The study enrolled subjects aged 60 years or older with a principal diagnosis of GAD into a 12-week, randomized trial of escitalopram versus placebo. One hundred fifty subjects were genotyped for the serotonin transporter promoter region haplotype and were divided into La? and La+ genotype groups; the primary analyses were done in European Americans only (n = 125; n = 59 with escitalopram and n = 66 with placebo). RESULTS:Escitalopram had no efficacy in the La? group versus moderate efficacy in the La+ group. This genetic moderation of SSRI efficacy was due to a higher placebo response in La? subjects, compared with La+ subjects. Drug concentration did not affect the genetic results. Exploratory analyses suggest that La? subjects had greater variability of anxiety symptoms unrelated to treatment. CONCLUSIONS:The serotonin transporter promoter haplotype is associated with variability in SSRI efficacy for late-life GAD. The variability may result from a genetic effect on anxiety symptom variability unrelated to treatment, rather than a pharmacodynamic effect that has been previously assumed. Further research is needed to understand the pharmacogenetic mechanism of this haplotype.

SUBMITTER: Lenze EJ

PROVIDER: S-EPMC3059101 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Relation of serotonin transporter genetic variation to efficacy of escitalopram for generalized anxiety disorder in older adults.

Lenze Eric J EJ Goate Alison M AM Nowotny Petra P Dixon David D Shi Peichang P Bies Robert R RR Lotrich Francis K FK Rollman Bruce L BL Shear M Katherine MK Thompson Paul A PA Andreescu Carmen C Pollock Bruce G BG

Journal of clinical psychopharmacology 20101201 6

<h4>Objective</h4>Generalized anxiety disorder (GAD) is common in older adults and can be treated with selective serotonin reuptake inhibitors (SSRIs). Genetic variation in the serotonin transporter gene promoter region is posited to be associated with SSRI efficacy: 2 polymorphisms (5-HTTLPR S/L and rs25531 g/a) form a haplotype with the La combination having higher transcription activity than other haplotypes. We hypothesized that GAD patients with no La haplotypes (La⁻) have lower SSRI treatm ...[more]

PMID: 21105279

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Project description:ContextGeneralized anxiety disorder (GAD) is one of the most common psychiatric disorders in older adults; however, few data exist to guide clinicians in efficacious and safe treatment. Selective serotonin reuptake inhibitors (SSRIs) are efficacious for younger adults with GAD, but benefits and risks may be different in older adults.ObjectiveTo examine the efficacy, safety, and tolerability of the SSRI escitalopram in older adults with GAD.Design, setting, and participantsA randomized controlled trial in primary care practices and related specialty clinics in Pittsburgh, Pennsylvania, of 177 participants aged 60 years or older with a principal diagnosis of GAD randomized to receive either escitalopram or placebo and conducted between January 2005 and January 2008.InterventionsTwelve weeks of 10 to 20 mg/d of escitalopram (n = 85) or matching placebo (n = 92).Main outcome measuresCumulative response defined by Clinical Global Impressions-Improvement score of much or very much improved; time to response; and anxiety and role functioning changes measured by the Clinical Global Impressions-Improvement scale, Hamilton Anxiety Rating Scale, Penn State Worry Questionnaire, Late-Life Function and Disability Instrument activity limitations subscale, and the role-emotional impairment and social function subscales of the Medical Outcome Survey 36-item Short Form.ResultsIn the primary analytic strategy in which participants (n = 33) were censored at the time of dropout, mean cumulative response rate for escitalopram was 69% (95% confidence interval [CI], 58%-80%) vs 51% (95% CI, 40%-62%) for placebo (P = .03). A conservative intention-to-treat analysis showed no difference in mean cumulative response rate between escitalopram and placebo (57%; 95% CI, 46%-67%; vs 45%; 95% CI, 35%-55%; P = .11). Participants treated with escitalopram showed greater improvement than with placebo in anxiety symptoms and role functioning (Clinical Global Impressions-Improvement scale: effect size, 0.93; 95% CI, 0.50-1.36; P < .001; Penn State Worry Questionnaire: 0.30; 95% CI, 0.23-0.48; P = .01; activity limitations: 0.32; 95% CI, 0.01-0.63; P = .04; and the role-emotional impairment and social function: 0.96; 95% CI, 0.03-1.90; P = .04). Adverse effects of escitalopram (P < .05 vs placebo) were fatigue or somnolence (35 patients [41.1%]), sleep disturbance (12 [14.1%]), and urinary symptoms (8 [9.4%]).ConclusionsOlder adults with GAD randomized to escitalopram had a higher cumulative response rate for improvement vs placebo over 12 weeks; however, response rates were not significantly different using an intention-to-treat analysis. Further study is required to assess efficacy and safety over longer treatment durations.Trial registrationclinicaltrials.gov Identifier: NCT00105586.

Project description:OBJECTIVE:To conduct a post hoc evaluation of the prevalence of clinically significant pain and the efficacy of duloxetine in patients with generalized anxiety disorder (GAD) and concurrent pain. METHOD:Data from two 9- to 10-week double-blind, placebo-controlled, randomized clinical trials of duloxetine (60 to 120 mg) in DSM-IV-defined GAD were analyzed (study 1 was conducted from July 2004 to September 2005; study 2 was conducted from August 2004 to June 2005). Efficacy was assessed with the Hamilton Rating Scale for Anxiety (HAM-A), visual analog scales (VAS) for pain, the Hospital Anxiety Depression Scale (HADS), the Clinical Global Impressions-Improvement of Illness (CGI-I) scale, the Patient Global Impressions-Improvement (PGI-I) scale, and the Sheehan Disability Scale (SDS) global functional impairment scale. RESULTS:Of 840 patients randomly assigned to treatment, 61.3% (302 duloxetine, 213 placebo) had VAS scores ? 30 mm on at least 1 of the pain scales, indicating clinically significant pain. Among those patients with concurrent pain at baseline, change from baseline to endpoint in the HAM-A total score (42.9% change in mean scores for duloxetine, 31.4% for placebo), HADS anxiety scale (40.3% vs. 22.8%), HADS depression scale (36.1% vs. 20.5%), HAM-A psychic factor (45.9% vs. 29.9%), and SDS global functional improvement score (45.5% vs. 22.1%) was significantly (all p's < .001) greater for duloxetine compared with placebo. Improvement on the CGI-I (p = .003) and PGI-I (p < .001) was also significantly greater for duloxetine. Response (HAM-A total score decrease ? 50%) (49% vs. 29%) and remission (HAM-A total score ? 7 at endpoint) (29% vs. 18%) rates were significantly greater for duloxetine compared with placebo (p < .001 and p = .041, respectively). Duloxetine demonstrated statistically significantly greater reduction in pain on all 6 VAS pain scales (all p's < .001 except headaches with p < .002) (for duloxetine, percent change in means from baseline to endpoint ranged from 40.1% to 45.2% across the 6 VAS scales; for placebo, 22.0% to 26.3%). CONCLUSION:Duloxetine, relative to placebo, improves anxiety symptoms, pain, and functional impairment among patients with GAD with concurrent clinically significant pain. TRIAL REGISTRATION:clinicaltrials.gov Identifiers: NCT00122824 (study 1) and NCT00475969 (study 2).

Dataset Information

Relation of serotonin transporter genetic variation to efficacy of escitalopram for generalized anxiety disorder in older adults.

Publications

Relation of serotonin transporter genetic variation to efficacy of escitalopram for generalized anxiety disorder in older adults.

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